Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease of unknown etiology; however, apoptosis of lung alveolar epithelial cells plays a role in disease progression. This intractable disease is associated with increased abundance of Staphylococcus and Streptococcus in the lungs, yet their roles in disease pathogenesis remain elusive. Here, we report that Staphylococcus nepalensis releases corisin, a peptide conserved in diverse staphylococci, to induce apoptosis of lung epithelial cells. The disease in mice exhibits acute exacerbation after intrapulmonary instillation of corisin or after lung infection with corisin-harboring S. nepalensis compared to untreated mice or mice infected with bacteria lacking corisin. Correspondingly, the lung corisin levels are significantly increased in human IPF patients with acute exacerbation compared to patients without disease exacerbation. Our results suggest that bacteria shedding corisin are involved in acute exacerbation of IPF, yielding insights to the molecular basis for the elevation of staphylococci in pulmonary fibrosis.
ABSTRACT-The effects of adenosine and its related compounds on the cholinergic twitch response were examined in electrically stimulated guinea pig ileum. Adenosine (3 x 10-'-10-5 M) and an adenosine A1-receptor agonist N6-cyclohexyladenosine (CHA, 10-8-10-6 M) suppressed the twitch. Conversely, the A2a receptor agonist 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS 21680, 10-9-10-7 M) potentiated the twitch in half the preparations examined. The A1-antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), which per se did not affect the twitch, recovered the attenuated twitch caused by CHA (10-' M) or adenosine (10-6 M) and converted it into a potentiated twitch. These results suggest the presence of adenosine A1-and A2a-receptors coupled negatively and positively, respectively, to acetylcholine release in the preparation.
Idiopathic pulmonary fibrosis (IPF) is a fatal disease with a median survival of 3-4 years after diagnosis. It is the most frequent form of a group of interstitial pneumonias of unknown etiology. Current available therapies prevent deterioration of lung function but no therapy has shown to improve survival. Periostin is a matricellular protein of the fasciclin 1 family. There is increased deposition of periostin in lung fibrotic tissues. Here we evaluated whether small interfering RNA or antisense oligonucleotide against periostin inhibits lung fibrosis by direct administration into the lung by intranasal route. Pulmonary fibrosis was induced with bleomycin and RNA therapeutics was administered during both acute and chronic phases of the disease. The levels of periostin and transforming growth factor-β1 in airway fluid and lung tissue, the deposition of collagen in lung tissue and the lung fibrosis score were significantly reduced in mice treated with siRNA and antisense against periostin compared to control mice. These findings suggest that direct administration of siRNA or antisense oligonucleotides against periostin into the lungs is a promising alternative therapeutic approach for the management of pulmonary fibrosis.
Idiopathic pulmonary fibrosis is an incurable disease of unknown etiology. Acute exacerbation of idiopathic pulmonary fibrosis is associated with high mortality. Excessive apoptosis of lung epithelial cells occurs in pulmonary fibrosis acute exacerbation. We recently identified corisin, a proapoptotic peptide that triggers acute exacerbation of pulmonary fibrosis. Here, we provide insights into the mechanism underlying the processing and release of corisin. Furthermore, we demonstrate that an anticorisin monoclonal antibody ameliorates lung fibrosis by significantly inhibiting acute exacerbation in the human transforming growth factorβ1 model and acute lung injury in the bleomycin model. By investigating the impact of the anticorisin monoclonal antibody in a general model of acute lung injury, we further unravel the potential of corisin to impact such diseases. These results underscore the role of corisin in the pathogenesis of acute exacerbation of pulmonary fibrosis and acute lung injury and provide a novel approach to treating this incurable disease.
ABSTRACT-Colonic motility was measured with three catheter pressure transducers that were inserted into the descending colon at the distance of 4 cm, 6 cm and 8 cm from the anal verge in anesthetized rats. Colonic infusion of glycerol (65%, 2 ml/kg) induced large phasic pressure changes with high amplitude and long duration. Some of the pressure changes propagated over all the three recording sites, appearing to be equivalent to giant migrating contractions. These glycerol-induced large propulsions were abolished by lido caine (5%, 2 ml/kg, intracolon), hexamethonium (10 mg/kg, i.v.) or clonidine (30 pg/kg, i.v.); and they were almost entirely suppressed by atropine (3 mg/kg, i.v.), suggesting the principal involvement of the cholinergic neural pathway.
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